Regenerative engineering for complex extremity trauma

复杂肢体创伤的再生工程

• 批准号: 10584227
• 负责人: Karina Nakayama
• 金额: $ 52.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584227
• 关键词: Aerobic Exercise; Affect; Age; Anisotropy; Biophysics; Blood flow; Bone Regeneration; Bone Tissue; Cause of Death; Cells; Clinical; Clinical Management; Clinical Treatment; Complex; Complication; Coupled; Coupling; Cues; Defect; Dependence; Deposition; Development; Endothelial Cells; Evaluation; Exercise; Extracellular Matrix; Fracture; Functional Regeneration; Gait; Gene Expression; Generations; Genomics; Guided Tissue Regeneration; Hospitalization; In Vitro; Individual; Inflammatory; Injury; Limb Salvage; Limb structure; Lower Extremity; Maintenance; Mediating; Mimetic Muscles; Motion; Mus; Muscle; Muscle Cells; Muscle Fibers; Musculoskeletal; Natural regeneration; Open Fractures; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Outcome; Pathway interactions; Pattern; Persons; Phenotype; Physical Rehabilitation; Physical therapy; Play; Production; Proteins; Proteome; Recovery; Recovery of Function; Regenerative engineering; Regimen; Regulation; Rehabilitation therapy; Research; Resistance; Role; Running; Series; Site; Skeletal Muscle; Skeletal system; Stains; Structure-Activity Relationship; Surgical Management; System; Tissues; Transplantation; Trauma; United States; War; Work; angiogenesis; bone; bone healing; bone marrow mesenchymal stem cell; bone repair; cell fate specification; collagen scaffold; comorbidity; composite restoration; disability; examination questions; functional restoration; healing; improved; in vivo; injury and repair; innovation; limb amputation; limb injury; mechanical load; microCT; mimetics; mouse model; muscle physiology; muscle regeneration; myogenesis; nanofibrillar; nanoscale; nerve supply; novel; osteogenic; paracrine; progenitor; programs; radiological imaging; regeneration potential; regenerative; regenerative approach; reinnervation; repaired; scaffold; severe injury; soft tissue; tibia; tibialis anterior muscle; tissue regeneration; Aerobic Exercise; Affect; Age; Anisotropy; Biophysics; Blood flow; Bone Regeneration; Bone Tissue; Cause of Death; Cells; Clinical; Clinical Management; Clinical Treatment; Complex; Complication; Coupled; Coupling; Cues; Defect; Dependence; Deposition; Development; Endothelial Cells; Evaluation; Exercise; Extracellular Matrix; Fracture; Functional Regeneration; Gait; Gene Expression; Generations; Genomics; Guided Tissue Regeneration; Hospitalization; In Vitro; Individual; Inflammatory; Injury; Limb Salvage; Limb structure; Lower Extremity; Maintenance; Mediating; Mimetic Muscles; Motion; Mus; Muscle; Muscle Cells; Muscle Fibers; Musculoskeletal; Natural regeneration; Open Fractures; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Outcome; Pathway interactions; Pattern; Persons; Phenotype; Physical Rehabilitation; Physical therapy; Play; Production; Proteins; Proteome; Recovery; Recovery of Function; Regenerative engineering; Regimen; Regulation; Rehabilitation therapy; Research; Resistance; Role; Running; Series; Site; Skeletal Muscle; Skeletal system; Stains; Structure-Activity Relationship; Surgical Management; System; Tissues; Transplantation; Trauma; United States; War; Work; angiogenesis; bone; bone healing; bone marrow mesenchymal stem cell; bone repair; cell fate specification; collagen scaffold; comorbidity; composite restoration; disability; examination questions; functional restoration; healing; improved; in vivo; injury and repair; innovation; limb amputation; limb injury; mechanical load; microCT; mimetics; mouse model; muscle physiology; muscle regeneration; myogenesis; nanofibrillar; nanoscale; nerve supply; novel; osteogenic; paracrine; progenitor; programs; radiological imaging; regeneration potential; regenerative; regenerative approach; reinnervation; repaired; scaffold; severe injury; soft tissue; tibia; tibialis anterior muscle; tissue regeneration

PROJECT SUMMARY The clinical treatment of limb threatening injuries requires complex surgical management and a lifetime of corrective surgeries and physical therapy. Advancements in the treatment of complex lower extremity trauma with composite tissue loss are hindered by the lack of available therapies that can functionally repair both muscle and adjacent bone. As a result of limited treatment options, composite injuries involving open bone fractures with concomitant soft tissue co-morbidities, are 4-5 times more likely to result in delayed or failed bone union. There is an unmet clinical need for regenerative approaches that can guide and restore the functional biophysical relationship within and between both tissues. Our prior research has shown that spatial patterning cues from nanoscale extracellular matrices modulate the cellular inflammatory phenotype, angiogenic potential, and skeletal muscle myogenesis. We have further shown that when these patterned materials are combined with running exercise, that large volumetric muscle injuries in mice can be regenerated and re-innervated comparable to native tissue. With emerging evidence of a regenerative dependency of bone outcomes on muscle cells and secreted factors, control over the muscle regenerative niche may be the key to improved bone and limb healing in the management of extremity trauma. We believe that nanoscale spatial patterning cues from anisotropic fibrillar scaffolds will enhance the regenerative potential of myogenic and osteogenic cells, leading to muscle and bone regeneration and functional restoration. This proposal first examines these questions in vitro to identify the role that spatial patterning plays in guiding cell fate specification of muscle and bone progenitors as well as bone marrow-derived mesenchymal stem cells. These studies will define the biophysical relationship between nanoscale patterning and subcellular regulation of tissue-specific cell phenotype. In parallel with these studies, paracrine regulation of osteogenesis by myogenic cells will be characterized in vitro and in vivo in a novel mouse model of composite injury of the tibia/tibialis anterior. Through the use of spatial patterning to enhance myogenesis, we aim to guide the crosstalk that occurs between muscle and bone during injury and repair to impact adjacent bone healing. Furthermore, physical rehabilitation is known to play a critical role in the successful physical recovery from lower extremity trauma by improving blood flow to damaged tissues and increasing strength recovery through mechanical loading. Our patterned scaffolds have been shown to synergistically work with exercise stimulation to improve healing following muscle trauma. Therefore, we will couple patterned scaffolds with running exercise to enhance local muscle and adjacent bone regeneration. Together, this body of work will establish a regeneratively robust and innovative approach for the treatment of complex extremity trauma with composite tissue loss.

项目摘要 肢体威胁伤害的临床治疗需要复杂的手术管理和一生 矫正手术和物理治疗。复杂下肢创伤治疗的进步 由于缺乏可以在功能上修复两种肌肉的可用疗法而阻碍了复合组织损失 和相邻的骨头。由于治疗方案有限，涉及开放骨折的复合损伤与 伴随的软组织合并症，导致骨骼延迟或失败的可能性高4-5倍。那里 是对可以指导和恢复功能生物物理的再生方法的临床需求 两组之间和之间的关系。 我们先前的研究表明，来自纳米级细胞外矩阵的空间图案提示调节 细胞炎症表型，血管生成潜力和骨骼肌肌发生。我们还有更多 表明，当这些图案化的材料与跑步运动结合在一起时 小鼠的损伤可以再生并重新发射与天然组织相当。有了新兴的证据 骨结果对肌肉细胞和分泌因素的再生依赖性，控制肌肉 再生生态位可能是肢体创伤管理中改善骨骼和肢体愈合的关键。 我们认为，来自各向异性纤维支架的纳米级空间图案提示将增强 肌原性和成骨细胞的再生潜力，导致肌肉和骨再生以及功能 恢复。该建议首先在体外检查这些问题，以确定空间图案的作用 指导肌肉和骨祖细胞以及骨髓衍生的间充质的细胞命运规范 干细胞。这些研究将定义纳米级图案与亚细胞的生物物理关系 调节组织特异性细胞表型。与这些研究并行，成骨的旁分泌调节 在新型的小鼠复合损伤模型中，由肌生成细胞在体外和体内进行表征 胫骨/胫骨前。通过使用空间图案来增强肌发生，我们旨在引导串扰 这发生在受伤和修复过程中肌肉和骨骼之间，以影响相邻的骨骼愈合。此外， 众所周知，身体康复在下肢成功的身体恢复中起着至关重要的作用 通过改善血液流向受损组织的创伤并通过机械增加强度恢复 加载中。我们的图案脚手架已被证明与运动刺激协同作用以改进 肌肉创伤后治愈。因此，我们将将图案的脚手架与跑步锻炼相结合以增强 局部肌肉和邻近的骨再生。这项工作将共同建立一个再生 和创新方法，用于治疗复合组织损失的复杂肢体创伤。